ABCB5 is a multidrug resistance transporter recently shown to be preferentially expressed by cells of melanocytic lineage and to be responsible for conferring resistance to chemotherapy in vitro. For example, inhibition of ABCB5 renders normally resistant melanoma cells susceptible to doxorubicin. Subsequent work has shown that ABCB5 expression 1) marks melanoma cells of stem cell phenotype and function; 2) correlates with tumorigenic growth of melanoma cells in vivo; and 3) is more abundant in human malignant melanoma than in benign melanocytic nevi. In tandem with fundamental approaches to further establishing ABCB5 as an identifier of melanoma stem cells (MF, separately funded), we here propose to explore the clinical relevance of ABCB5 as a biomarker of melanoma progression, prognosis, and outcome, as well as to demonstrate the therapeutic efficacy of ABCB5 targeting in a relevant animal model of human malignant melanoma. The technologies that will be employed to accomplish these goals range from tissue microarrays to detailed analysis of primary human melanomas supported by prognostic and outcome data to a SCID mouse bioassay in which melanomas develop in xenografted human skin in a manner that recapitulates naturally-occurring disease and in which ABCB5+ tumor cells may be therapeutically targeted. In sum, these approaches will determine the clinical relevance and therapeutic importance of this novel biomarker, and should pave the way to eventual clinical therapeutic trials focused on targeting of ABCB5* melanoma stem cells.